This subject is not really news anymore, but I am writing about it to
call attention to a review article, VNS
Therapy in Treatment-Resistant Depression: Clinical Evidence and
Putative Neurobiological Mechanisms. In this post,
I provide a little overview of VNS therapy, comment on some other
sources of information, and say a little bit about where I would like
the research to go next.
VNS Therapy in Treatment-Resistant
Evidence and Putative Neurobiological Mechanisms
Charles B Nemeroff*,1,2, Helen S Mayberg2, Scott E
Krahl3, James McNamara4, Alan Frazer5,
Thomas R Henry2, Mark S George6, Dennis S Charney7 and
Stephen K Brannan8
Currently available therapeutic interventions for treatment-resistant
depression, including switch, combination, and augmentation strategies,
are less than ideal. Observations of mood elevation during vagus nerve
stimulation (VNS) therapy for pharmacoresistant
epilepsy suggested a role for VNS therapy in refractory major
depression and prompted clinical investigation of this neurostimulation
modality. The VNS Therapy Systemt has been available for treatment of
pharmacoresistant epilepsy since 1997 and was approved by
the US Food and Drug Administration for treatment-resistant depression
in July, 2005. The physiology of the vagus nerve, mechanics of the VNS
Therapy System, and efficacy and safety in pharmacoresistant epilepsy
are reviewed. Promising results of VNS therapy for treatment-resistant
depression have been forthcoming from both acute and long-term studies,
evidenced in part by progressive improvements in depression rating
scale scores during the 1st year of treatment with maintenance of
response thereafter. VNS therapy is well tolerated in patients with
either pharmacoresistant epilepsy or treatment-resistant depression. As
in epilepsy, the mechanisms of
VNS therapy of treatment-resistant depression are incompletely
understood. However, evidence from neuroimaging and other studies
suggests that VNS therapy acts via innervation of the nucleus tractus
solitarius, with secondary projections to limbic and cortical
structures that are involved in mood regulation, including brainstem
regions that contain serotonergic (raphe nucleus) and noradrenergic
(locus ceruleus) perikarya that project to the forebrain. Mechanisms
that mediate the beneficial effects of VNS therapy for treatment
resistant depression remain obscure. Suggestions for future research
directions are described.
Neuropsychopharmacology (2006) 31, 1345–1355.
The vagus nerve
is one of the twelve pairs of nerves that comes out of the brain and
goes to some body part more or less directly, rather than going
through the spinal cord. The vagus nerve, in particular,
runs through the neck and into the chest. It does a wide
variety of things, although none of its known functions has anything to
do with emotional regulation. The reason I mention that, is
that I find it fascinating that electrical stimulation of a nerve could
have such a profound effect on something that does not appear
to be related to the function of the nerve.
VNS therapy originated as a treatment for
epilepsy that was refractory to treatment with medications.
Early studies indicated that some patients with both epilepsy
and depression experienced improvement in their depression as well as
In order to undergo this treatment, patients have to have a
pacemaker-like device implanted in their chest. It costs
about $15,000. For these reasons, it is not something that is
It is not a quick fix, and it does not always work. In the
first ten weeks, about 30% of patients have at least a 50%
reduction in symptoms, and about 15% experience remission.
The mean time to response in 48 days. (Response
is defined as a 50% reduction in symptoms.)
After one year, the response rate is 44%. After two years,
the response rate is 42%.
In is important to note, however, that patients do not need to have a
response in order to benefit. At first, that seems like a
nonsensical statement. However, remember that the word response
is used here in a technical sense. Even a 25% reduction in
symptoms can make a big difference in a person’s life. It
could make a difference between being employed or being on disability,
or being married versus getting divorced.
As with epilepsy, the mechanisms by which VNS therapy
may benefit treatment-resistant depression are presently unclear.
Even so, there is a lot that is known, and the article lays it out
Perhaps just as interesting from a public-interest perspective is the
fact that one of the recipients of the treatment, Charles E.
Donovan III, has written a book about his experience, Out of
the Black Hole. Also, one can get additional
perspective by reading the reader comments on the Amazon
page for the book. He has a blog here.
The Nemeroff article ends with some suggestions for future research.
I found that section to be a little disappointing.
Although they have good suggestions, the suggestions mostly
are oriented toward optimizing the effectiveness of the treatment.
As a clinician, though, I do not see a suggestion for what I
anticipate would be my most frequent problem.
In considering what patients to refer for consideration of VNS
treatment, I would want to know this: does the presence of personality
disorder or substance abuse disorder influence the probability of
If the safety profile and clinical effectiveness are borne out in
widespread use, VNS treatment will be an important advance.
It also has the potential to teach us a great deal about the
pathophysiology of depression. I suspect that there will be
advances in the basic sciences of neurobiology, and physiology in
general. But even a full understanding of those fields will
leave us with the nettlesome problem of how to select patients
They do offer one suggestion in that area:
Can predictors of response to VNS therapy in
depressed patients be identified by functional imaging or genetic
That would be helpful, but frankly, I do not have much hope that it
will pan out. Based upon our experience so far with attempts
at treatment matching, I am fairly sure that in the near future,
patient selection will be on clinical grounds only. The most
difficult decisions will be for those patients with depression and
personality disorder, or depression and substance